Opioids

DRUGS INCLUDED IN THIS CATEGORY

Morphine

Codeine

Heroin

Pethidine (meperidine)

Diphenoxylate

Fentanyl

Methadone

Oxycodone

Pentazocine

(Dextro)propoxyphene

Buprenorphine

OVERVIEW

Opioids present with a syndrome which includes miosis, coma, respiratory depression and vomiting. A rapid response to naloxone is usual if hypoxic brain damage or other events have not been superimposed. The treatment is primarily supportive, although naloxone may also be used in certain circumstances. In recreational overdoses (i.e. dependent patients), a withdrawal reaction to non-titrated doses naloxone is common

MECHANISM OF TOXICITY EFFECTS

Opioids are opioid receptor agonists. Stimulation of these receptors in the central nervous systems leads to analgesia, vomiting and profound sedation in a dose dependent manner. These effects are potentiated by other sedative drugs (e.g. alcohol, benzodiazepines) and the majority of fatal overdoses involve other substances. Non-cardiogenic pulmonary oedema occurs in a substantial number of opioid overdoses, however the mechanism behind this is unknown. Dextropropoxyphene and its metabolite norpropoxyphene have 'antiarrhythmic' (and consequently proarrhythmic) activity. This may lead to arrhythmias and negative inotropic effects. Pethidine and pentazocine have serotonergic effects in addition to their opioid effects and, usually in combination with other drugs, may cause the serotonin syndrome

KINETICS IN OVERDOSE

The opioids are a diverse group of substances. The most important kinetic difference between them is their half-life in overdose which varies from hours to days.

Absorption

Opioids are generally rapidly absorbed, with peak concentrations within two hours of oral ingestion, one hour of IM administration and minutes of IV injection. First pass metabolism is noted with some of these drugs (codeine, morphine, propoxyphene) however these drugs also have active metabolites. Oral controlled release formulations of morphine and oxycodone and topical preparations of fentanyl are also available and are frequently used in palliative care. Absorption from these preparations will continue for up to 12 hours.
Buprenorphine is used as opiate replacement therapy and administered sublingually.

Distribution

These drugs have volumes of distribution of 1-5 L/kg and cross well into the central nervous system.

Metabolism - Elimination

These drugs are primarily hepatically metabolised. The half-life of most of these drugs is between 1 and 5 hours. However methadone (about 20 to 60 hours), buprenorphine (about 35 hours S/L; 1-7 hours IV) and propoxyphene (12 to 24 hours) are exceptions.

CLINICAL EFFECTS

Central nervous system

CNS depression is the major clinical manifestation. Increasing doses lead to increasing degrees of sedation with initial analgesia and sedation, followed by loss of response to verbal stimuli, loss of response to tactile stimuli, loss of control over normal respiration and failure of temperature and blood pressure regulation.

Cardiac

Dextropropoxyphene may lead to cardiac effects and ECG changes. The ECG changes seen in propoxyphene overdose are similar to those seen in tricyclic antidepressant poisoning <TCAs.htm> with QRS and QT prolongation, varying degrees of heart block and tachyarrhythmias.
Methadone can the prolongs QT interval and cause torsades de pointes..

Pulmonary

Aspiration and non-cardiogenic pulmonary oedema <Pulmonary%20oedema.htm> are acute common complications.

Other

INVESTIGATIONS

Imaging

A chest X-ray should be obtained in severe opioid overdose as aspiration and non-cardiogenic pulmonary oedema <Pulmonary%20oedema.htm> are common complications.

ECG

An ECG should be done in overdoses involving propoxyphene and methadone.

Blood concentrations

Drug concentrations are not helpful in the management of overdose.

Urine drug screen

Patients with recreational overdoses should have a urine drug screen for drugs of abuse to identify other substances that may have been taken or abused but is not helpful in the management of an acute overdose.

Other investigations

Patients with suicidal ingestions who present with an opioid syndrome should have paracetamol, salicylate and electrolytes done to detect coingestion of paracetamol and/or aspirin , as combination tablets are a frequent source of codeine or propoxyphene.In patients abusing ibuprofen/codeine combinations renal tubular acidosis and/or gastropothy may be seen

DIFFERENTIAL DIAGNOSIS

The differential diagnosis for a patient presenting with a typical opioid syndrome is any other sedating drug. The presence of miosis is not limited to opioid drug overdose but occurs in benzodiazepine , chloral hydrate, barbiturate, phenothiazine , alcohol, GHB, clonidine and organophosphate overdose. A failure to respond to naloxone indicates ingestion (or coingestion) of one of these other drugs is more
likely.

DIFFERENCES IN TOXICITY

Prolonged toxicity is seen following exposure to agents:

with long half lifes eg methadone, buphenorphine and propoxyphene

controlled release preparations

Transdermal patches

Propoxyphene may cause direct cardiac effects.

Drugs such as codeine, which are prodrugs, have much less toxicity in overdose as they need to be converted to more active metabolites. Drugs administered by the intravenous route in recreational overdoses may involve various adulterants which occasionally will be of clinical importance.

Unexplained symptoms in patients with recreational overdose should prompt a search for these substances and should include an ECG to detect cardiotoxic drugs.

TREATMENT

Supportive

Management of opioid toxicity is centered on the maintenance of respiration and cardiopulmonary function, as well as appropriate use of an opioid antagonist.
Patients should be closely observed for the development of respiratory depression. If necessary, naloxone can be given to counteract the sedating effect of opioids. Intubation and ventilation will occasionally be required for patients who have developed respiratory complications of their overdose.

GI Decontamination

Gastric decontamination is effective, particularly in those ingesting sustained released forms. After eliminating the existence of potential contraindications such as ileus, activated charcoal can be administered up to 4 hours post-ingestion of a standard release formulation or up to 12 hours after a sustained release formulation.
Consider whole bowel irrigation in sustained release preparations.
Enhanced elimination techniques to increase the rate of removal of opioids are not recommended.

Antidotes

Naloxone

Mechanism
Naloxone is an opiate receptor antagonist with a short half life. The duration of action of a single dose is usually less than 1-2 hours. As this is shorter than the duration of action of most opioids, repeat doses are often required to maintain consciousness.
Indications include diminished respirations (less than or equal to 12 per minute), with pinpoint pupils, reduced level of consciousness or evidence of opiate use.
Naloxone may be administered via the intravenous, intramuscular, subcutaneous, intranasal, intratracheal, or sublingual routes.
There is good evidence now that intranasal administration (1mg per nostril via an atomisation device) is effective and can avoid the use of needles in this high risk group of patients.

Dose
Naloxone is given 0.1- 0.4 mg IV or IM repeated every 2-3 minutes up to a total dose of 2 mg. Larger doses of up to 12 mgs may be needed for buphrenorpine
Failure to respond to 2 mg means further doses are unlikely to be helpful. Use the minimum dose necessary to raise the patient's level of consciousness to a point where respiratory depression is avoided and the patient may be woken.
Too large a dose of naloxone may not only precipitate opioid withdrawal, but may lead to the patient absconding and of risk of later deterioration. (see Coroner/Medical Examiner).
If the patient is not opiate dependent, may use larger doses 0.4-2mg boluses.

Monitoring and infusions
Patients should be observed carefully for relapse for at least 2-3 hours. If a patient does redevelop marked sedation after their first naloxone dose, an infusion of naloxone may be required (commencing with a dose that is half to two thirds of the dose required initially to wake them given per hour).
Titrate infusion rate to response.
pCO_2 estimation is the most accurate way to assess respiratory depression due to opioids and should be regularly measured in patients on infusions.
Controlled release morphine and oxycodone, methadone and propoxyphene overdoses may require a continuous infusion for as long as several days.

Adverse effects
Over-administration of an opioid antagonist may precipitate a withdrawal syndrome in the opioid dependent with onset of agitation, hypertension, tachycardia, emesis, and/or pulmonary aspiration.
In patients suspected of opioid dependence it is important to titrate doses of naloxone to reverse respiratory depression only, rather than achieve full reversal of drug effect.
Opioid antagonists produces few adverse effects in non-opioid dependent patients, even at high dosages.
There are reports relating naloxone use with a range of adverse effects including; non-cardiogenic pulmonary edema, cardiac dysrhythmia, and hypertension. However these have not been confirmed as definitely due to the antidote.

Treatment of specific complications

Propoxyphene induced arrhythmias
Patients ingesting propoxyphene with abnormal ECGs (increased PR, QRS & QT durations) should be monitored until the ECG returns to normal. Treatment of tachy- and bradyarrhythmias should be similar to that used in TCA poisoning with alkalinisation as the first line therapy.

LATE COMPLICATIONS- FOLLOW UP

Patients with recreational overdoses should be referred to drug and alcohol services. If the patient is not sedated and has not received naloxone within the previous three hours, the patient may be discharged. Patients with propoxyphene overdoses should have ECG monitoring until their ECG returns to normal. Long term sequelae are only likely if there has been a period of hypoxia with subsequent hypoxic brain injury.